Compounds comprising polycyclic chromophores bearing a flexible cationic side chain have been known to show cytotoxic effects and to possess utility as anticancer drugs.
Tricyclic chromophores that show cytotoxic activity include benzoisoquinolinediones (e.g., amonafide, 1; Asbury et al., 1998; Leaf et al., 1997), acridine-4-carboxamides (e.g., DACA, 2; Atwell et al., 1987; Baguley et al., 1995; U.S. Pat. No. 4,590,277) and anthraquinones (e.g., mitoxantrone, 3; Koller et al., 1999).
Tetracyclic chromophores with cytotoxic activity include anthrapyrazoles (e.g., losoxantrone, 4; Diab et al., 1999; Judson, 1992), indeno[2,1-c]quinolin-7-ones (e.g., TAS-103, 5; Utsugi et al., 1996), benzophenazines (e.g., XR-11576, 6; Vicker et al., 2002), azonafides (e.g. 7; Sami et al., 1996), imidazoacridinones (e.g. 8; Cholody et al., 1996), pyrimido[5,6,1-de]acridines (e.g. 9; Antonini et al., 1995), benzo[e]pyrido[4,3-b]indoles (e.g., intoplicine, 10; Riou et al., 1993), indeno[1,2-b]quinolines (e.g. 11, Deady et al., 1997) and benzo[e]perimidines (e.g. 12, Stefanska et al., 1993).
Many compounds where two such chromophores are linked by a flexible chain are also effective cytotoxins and anticancer drugs. For example, the bis(naphthalimide) DMP840, 13, was evaluated clinically (Thompson et al., 1998), bis(imidazoacridones) (e.g., WMC-26, 14; Cholody et al. 1995) and bis(phenazines) (e.g., XR5944, 15; Gamage et al., 2001; Stewart et al., 2001) are being considered for clinical trial.
From the publications referred to above, it can be seen that these compounds have a wide variety of different structures. They are considered to be active as anticancer drugs primarily through their ability to inhibit topoisomerase enzymes. However, the relationships between structure, the ability to inhibit topoisomerase enzymes and their potential utility as in vivo anticancer drugs are still not sufficiently well-defined to enable predictions to be made about activity. In view of the potential utility of such compounds, further classes of these compounds are needed.
The present invention relates to amide- (and thioamide) derivatives of benzo[b][1,6]naphthyridin-1 (2H)-one, their synthesis, and their use in the treatment of cancers. The benzo[b][1,6]naphthyridin-1 (2H)-one chromophore (Deady and Rodemann, 2001) and the N2- and carbon-substituted analogues (Asherson and Young, 1977; Khattab, 1996; Meth-Cohn, 1987; Rivalle and Bisagni, 1980) are known including the 6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid (Deady and Rodemann, 2001). Dibenzo[b,h][1,6]naphthyridin-6 (5H)-ones have also been reported (Asherson and Young, 1977; Vijayalakshmi and Rajendran, 1994). However, these reports concern the synthesis of the compounds only.
It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.
We have now synthesised and evaluated a novel series of carboxamide linked compounds based on benzo[b][1,6]naphthyridin-1 (2H)-one, which differ from previous acridine based compounds by the incorporation of a lactam or thiolactam function in one of the outer rings.
Representative examples of these compounds have utility as cytotoxic and anti-cancer agents.